Excessive alcohol consumption is a worldwide problem. There is increasing evidence in recent years to suggest that genetic factors play an important role in the development of alcohol drinking behaviors. The cAMP-responsive element binding (CREB) protein is the common denominator of signaling cascades for a number of neurotransmitter receptors, and is regulated via phosphorylation by several protein kinases. Phosphorylated CREB regulates the downstream expression of cAMP-inducible genes such as neuropeptide Y (NPY) and its receptor NPY-Y1 as well as brain-derived neurotrophic factor (BDNF). Several lines of evidence support the notion that these CREB related genes may be associated with alcohol-drinking behaviors. However, the interactive role of NPY and BDNF genes, mediated via CREB gene transcription factor, in alcohol preference is unknown. The goals of the proposed studies are to examine the role of CREB related target genes in alcohol-drinking behaviors using CREB-knock out mice. Our proposal is based on the hypothesis that decreased function of NPY and BDNF due to deletion of CREB gene transcription factor in the brain is responsible for the genetic predisposition to alcohol-drinking behaviors. The following Specific Aims will test this hypothesis: 1) To evaluate a) whether intracerebroventricular (ICV) infusions of NPY attenuate alcohol preference in CREB knock out (-/- and +/-) mice; and b) if the effects of NPY on alcohol preference are blocked by co-infusion with NPY-Y1 receptor antagonist. 2) To evaluate a) whether ICV infusions of BDNF attenuate alcohol preference in CREB knock out (-/- and +/) mice, and b) if the effects of BDNF on alcohol preference are blocked by co-infusion with NPY-Y1 receptor antagonist. This exploratory grant will establish that CREB knock out mice are a useful model to study the interactions of CREB related genes and their roles in alcohol drinking behaviors. The results from these studies will provide direct evidence that CREB-related target genes might be potential molecular loci for developing future drugs to treat or prevent alcohol-drinking behaviors. [unreadable] [unreadable]